1. Field of the Invention
This invention is directed to a biocompatible, hemostatic cross-linked gelatin composition comprising cross-linked gelatin and a sufficient amount of wetting agent to permit uniform wetting of the gelatin in the presence of an aqueous solution. This invention is further directed towards methods of decreasing the hydration time of cross-linked gelatin by incorporating a biocompatible wetting agent into the gelatin. This invention further relates to a kit of parts for preparing a biocompatible, hemostatic cross-linked gelatin composition comprising a sterile syringe and non-hydrated, biocompatible, pledget comprising a cross-linked gelatin and a wetting agent.
2. References
The following patent applications and patents are cited and/or referenced in this application as superscript numbers:                1Correll, et al., Proc. Soc. Exp. Biol. N.Y., 58:233 (1945).        2Correll, et al., Surg. Gyn. and Obst., 82:585 (1945).        3Correll, et al., U.S. Pat. No. 2,465,357, Therapeutic Sponge and Method of Making, issued Mar. 29, 1949.        4Correll, et al., U.S. Pat. No. 2,507,244, Surgical Gelatin Dusting Powder and Process for Preparing Same, issued May 9, 1950.        5Studer, et al., U.S. Pat. No. 2,558,395, Undenatured Gelatin Hemostatic Sponge Containing Thrombin, issued Jun. 26, 1951.        6Sieger, et al., U.S. Pat. No. 2,899,362, Hemostatic Sponges and Method of Preparing Same, issued Aug. 11, 1959.        7Song, et al., U.S. Pat. No. 5,399,361, Collagen-containing Sponges as Drug Delivery Compositions for Proteins, issued Mar. 21 1995.        
8Cragg, et al., U.S. Pat. No. 6,071,301, Device and Method for Facilitating Hemostasis of a Biopsy Tract, issued Jun. 6, 2000.                9Cragg, et al., U.S. Pat. No. 6,086,607, Device and Method for Facilitating Hemostasis of a Biopsy Tract, issued Jul. 11, 2000.        10Cragg, et al., U.S. Pat. No. 6,162,192, System and Method for Facilitating Hemostasis of Blood Vessel Punctures with Absorbable Sponge, issued Dec. 19, 2000.        11Pawelchak, et al., U.S. Pat. No. 4,292,972, Lyophilized Hydrocolloid Foam, issued Oct. 6, 1981.        12Sawyer, U.S. Pat. No. 4,238,480, Method for Preparing an Improved Hemostatic Agent and Method of Employing the Same, issued Dec. 9, 1980.        13Sawyer, U.S. Pat. No. 4,404,970, Hemostatic Article and Method for Preparing and Employing the Same, issued Sep. 20, 1983.        
All of the above references are herein incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Cross-linked gelatin, often in the form of gelatin foam, gelatin film or gelatin sponges, has been used as a hemostatic agent since its development by Correll in 1945.sup.1-4 Such hemostatic sponges or foams are used routinely to pack wounds, absorb blood and stop bleeding. They are often left in place to be bioabsorbed over a period of weeks to months. In addition, medicaments, such as antibiotics, growth factors and thrombus enhancing agents, have been incorporated into the cross-linked gelatin to enhance the in vivo properties of the composition.sup.5-7
To use, the hemostatic sponge is placed onto or into the wound, whereupon it absorbs blood or other fluids, expands to pack and compress the wound, and initiates a rapid clotting response. However, to achieve complete fluid absorption, rapid expansion, effective wound compression, and vigorous clotting action, the sponge must first be pre-hydrated or wetted, usually with sterile saline, before placement in the wound. This pre-hydration step, often accompanied with gentle compression and/or massaging of the sponge, can be time consuming and troublesome, often yielding non-uniform results at a critical moment in patient care. (See, for example, Directions for Use provided with Gelfoam®—available from Pharmacia Upjohn).
The hydrated sponge can then be compressed by hand and inserted or tamped into the wound. One particular wound suitable for use by hydrated sponges is a puncture site such as a puncture wound resulting from catheter insertion or a biopsy needle. When so used, the art describes ejection of a pledget of cross-linked gelatin from a syringe into the puncture site.sup.8-10
Critical to the ejection process is the flowability of the pledget from the syringe assembly and retention of its structural integrity during insertion into the body. Specifically, ejection of the pledget from the syringe assembly is preferably conducted with, at most, moderate pressure to ensure accurate placement in vivo. Efficient ejection of the pledget, in turn, relates to the flowability of the cross-linked gelatin through the syringe assembly. Higher fluid content pledgets are believed to correlate with enhanced flowability and, accordingly, it is desirable to maintain as high a fluid absorbability content in the sterilized pledget as possible.
Likewise, it is critical that the structural integrity of the pledget is substantially maintained as it is ejected from the syringe assembly when placed in vivo in order to ensure that portions of the pledget are not torn or otherwise separated from the pledget. This criticality is particularly important when the pledget is placed over a blood vessel puncture in order to avoid unintended thrombosis of the vessel. Structural integrity of the gelatin composition of the pledget under pressure is believed to correlate with the tensile strength of the composition and, accordingly, it is desirable to maintain as high a tensile strength in the sterilized pledget as possible.
In addition, it is desirable to perform hydration of the pledgets in the sterile environment of an injection syringe or syringe assembly by addition of a sterile saline solution to the syringe. Such a hydration process is complicated by the potential of distortions in the pledget due to a lack of uniformity and consistency in the rate of hydration of the pledget. Such distortions could cause unanticipated difficulties in fitting the pledget into the identified wound, e.g., puncture. In addition, the length of time normally needed to hydrate the pledget would typically prohibit such a hydration process. Accordingly, it is desired to obtain a quicker, more uniform hydration of the pledget to ensure predictability of the size and shape of the pledget and to facilitate hydration of the pledget inside the injection syringe.